18-amino progesterones and their manufacture



United States Patent 3,033,871 IS-ANIINO PRGGESTERONES AND THEIR ACTURE Oskar Jeger, Zurich, Switzerland, assignor to Ciba Pharmaceutical Products Inc, Summit, NJ. No Drawing. Filed June 17, 1960, Ser. No. 36,741 Claims priority, application Switzerland June 17, 1959 8 Claims. (Ci. 260-3973) This invention is based on the observation that 18- amino-progesterones and N-acyl-derivatives thereof can be made in a simple manner by reacting a A -18:20- imino-3-keto-pregnadiene with an organic acid halide in the presence of an alkali, and, if desired, hydrolyzing the resulting N-acyl-derivative to form the lS-amino-progesterone derivative and converting the latter into a salt thereof.

The process may be represented as follows:

CH N% Acyl-IFH (1H3 NH: (VHS I CH2 C0 CH2 CO Acyl-lTIH CH: 00

R-CHs-NH CHaOH 6H: (I HOH hydrolysis Rnschig process: 1. (COOCHQgNaOCH; 2. 1,; KO Ac 3. KO Ac water. The reaction is usually carried out at room'tem CHzN (CH2) dn 1. Tosylchloride 7 2 HN(CH3):

In carrying out the process of the invention the start ing material is reacted with an organic carboxylic or sulfonic acid halide, for example, acetyl, propionyl, butyryl or benzoyl chloride or bromide, p-toluene sulfonyl chloride, b'enzenesulfonyl chloride, methane sulfonyl chloride,-

in the presence of an aqueous alkali, for example, sodium hydroxide or potassium hydroxide.- As solvent there is used a base, such as pyridine, which is miscible with perature and there is obtained as reaction product the 18-acylamino-20-ketone corresponding to the starting material. The product can be converted by acid or alkalinehydrolysis into an 18amino-progesterone and the latter may be converted into a salt thereof, for example, the

hydrochloride, hydrobromide, sulfate, methane sulfonate,.

picrate etc.

As starting materials A -18:20-imino-3-keto-pregna-.

dienes unsubstituted in 2l-position and their 3-keto-derivatives are used. They may contain substituents such as free or functionally converted hydroxyl or oxo;groups,:

halogen atoms, alkyl, such as methyl groups, for example also in positions 1, 2, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16

and 17. By functionally converted hydroxyl or 0x0 groups there may be understood esterified or etherified hydroxyl groups or ketalized or enolized oxo groups or oximes, hydrazones or semicarbazones. The starting materials may also contain further double bonds, for example in positions 9, 11 or 14.

The following examples illustrate the invention:

Example 1 39 milligrams of A -18:20-imino-3-keto-pregnadiene melting at 187 C. are dissolved in a mixture of 2 cc. of pyridine, 0.5 cc. of water and 400 milligrams of potassium hydroxide, and to the solution there is added at room temperature dropwise, while stirring, 0.4 cc. of benzoyl chloride dissolved in 2 cc. of pyridine and 0.5 cc. of water. After 18 hours the mixture is taken up in ether and the ethereal solution is exhaustively washed Patented May s, 1962 I with water, tartaric acid solution of 10% strength, and

unchanged starting material.

*For the purpose of purification the neutral constituents are dissolved in 20 cc. of .a mixture of benzene and petroleum ether (1:1) and the solution is filtered through 'a column of 6 grams of aluminum oxide (activity II).

By means of the same solvent mixture a total of 58 milligrams of crystals melting at 185-186" C. can be eluted from the column, which corresponds to a yield of crude material amounting to 58% ofthe theoretical yield calculated on the starting material that undergoes reaction.

For the purpose of analysis a product having a constant melting point of 191-192 C. is prepared. by recrystallization from a mixture of acetone and petroleum ether. The product has the specific rotation [a] '=-+24-5 (c=1.45 in chloroiorm), infra-red bands (in chloroform) at 3400 emf- (NH-group), 1695 cm. (C-20 carbonyl), 1668 cm.- (CONH) and 1659/1619 cm. (MB-unsaturated lretone-grouping of the ring A). Ultra-violet spectrum (in ethanol): maximum at'239 mu, loge=4.24.

C H O N. Calculated: C, 77.56; H, 8.14%. Found: C, 77.38; H, 8.00%. V

The product is 1S-benzoylanfino-progesterone.

By carrying out the reaction with another acid halide, for example, acetyl chloride, the corresponding lS-acylamino-progesterone, for example, l8-acetyl-amino-progesteronc, is obtained.

The l8-acylamino-progesterones so obtained can be converted by hydrolysis into the l8-amino-progesterone and the latter may be converted into a salt thereof, for example, its hydrochloride.

Example 2 r 400 milligrams of M -18,20-imino-3-keto-pregnadiene (*1), dissolved in 6 ml. of pyridine, are admixed with 400 mg. of potassium hydroxide in 6 ml. of water, and 470 mg. of .para-tolueuesulfonic acid introduced in portions in the course of 20 minutes into the resulting mixture. The mixture is mechanically shaken overnight at 20 C., then acidified with 20% hydrochloric acid (until an acid reaction to Congo red is obtained) and the neutral portion taken up in benzene. Thereare thus obtained 230 mg. of a basic portion which according to melting point and mixed melting point is identified as starting material, and250 mg. .of neutral products (-l% calculated on reacted material). On repeated recrystallization of these neutral constituents from methanol or benzene there are obtained 150 mg. of crystals of melting point 142-143 C. In .me'uv spectrum they exhibit a maximum at 233 my (10ge=4.'26) .(in ethanol) and in the'lR'specti-um bands 'at 3280, 3000, 1705, 1670 and yield,

1620 cm: (in chloroform). The product is the 18- para-tosylamino-progesterone (l1 What is claimed is:

1. Process for the manufacture of 18-acyl-amino-pregnenes, wherein a member selected from the group con- 1 sisting of a A -18:ZO imino-3-keto-pregnadiene unsubstituted in the 2l-position and a 3-keto-derivative thereof selected from the group consisting of ketals, enols, oximes, hydrazones and semicarbazones is reacted with an organic acid halide in the presence of an alkali.

2. Process as claimed in claim 1, wherein the reaction is carried out with benzoyl chloride in the presence of a member selected from the group consisting of sodium and potassium hydroxide in an aqueous medium.

3. Process as claimed in claim 1, wherein the 18-acy1- amino-pregnene compound obtained is hydrolyzed to form the free IS-amino-pregnene compound;

4. Process as claimed in claim 3, wherein the free 18- amino compound is salified with an acid.

5. A compound selected from the group consisting of an 18-amino-progesterone, its acid addition salts, corresponding' 3-keto derivatives selected from the group con- No references cited.

sisting of ketals, enols, oxirnes, hydrazones and semi- UNITED STATES PATENT OFFICE CERTIFICATE F CORRECTION Patent No. 3,033,871 May 8, 1962 Oskar Jeger It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, formula A, upper right-hand portion, for

"CH N(CH read CH N(CH same column 2, line 59, for "39" rear] 93 column 3, line 41, afeg cid" insert chloride column 4, line 28, for "A z 0: read Signed and sealed this 11th day of September 1962.

(SEAL) Attest:

ERNEST w. SWIDER DAVID LADD Attesting Officer Commissioner of Patents 

1. PROCESS FOR THE MANUFACTURE OF 18-ACYL-AMINO-PREGNENES, WHEREIN A MEMBER SELECTED FROM THE GROUP CONSISTING OF A $4:20N-18:20-IMINO-3-KETO-PREGNADIENE UNSUBSTITUTED IN THE 21-POSITION AND A 3-KETO-DERIVATIVE THEREOF SELECTED FROM THE GROUP CONSISTING OF KETALS, ENOLS, OXIMES, HYDRAZONES AND SEMICARBAZONES IS REACTED WITH AN ORGANIC ACID HALIDE IN THE PRESENCE OF AN ALKALI.
 6. 18-AMINO-PROGESTERONE. 